It has recently been reported that a remarkable reduction in a plasma cholesterol level is observed when apolipoprotein E is administered intravenously to WHHL rabbit which is a model animal for human familial hypercholesterolemia homozygote (see Yamada et al., Proc. Natl. Acad. Sci. U.S.A., Vol. 86, pp. 665-669, (1989)), and also that plasma cholesterol and triglyceride are remarkably decreased by transducing a gene of apolipoprotein E into a mouse liver and expressing apolipoprotein E in a large quantity (see Shimano, H. et al., Journal of Clinical Investigation, Vol. 90, pp. 2084-2091, (1992)).
As reported in these references, an increase in plasma apolipoprotein E level has been extremely effective as a method for the treatment of hyperlipemia, especially familial hypercholesterolemia homozygote which has been considered to be difficult to treat with prior drugs.
Activators of cerebral circulation and metabolism have been mainly used as an agent for the treatment of senile dementia, but they do not exhibit any improved effect on a disintegration of the central nervous system which is considered to be the cause of senile dementia. On the other hand, it has been reported that apolipoprotein E may be expressed at a high level in the site of nervous system which is injured and being recovered (for example, see M. J. Ignatius et al., Proc. Natl. Acad. Sci. U.S.A., 83, 1125, (1986)), which suggests that apolipoprotein E will play an important role in repairing the nervous system.
Recently, comparative studies of the neuronal metabolism and function in apolipoprotein E-deficient mice and control mice have revealed that a selective degeneration of the central nervous system is observed in apolipoprotin E-deficient mice and this is remarkably similar to the selective degeneration of the neuronal system observed in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (see S. Chapman and D. M. Michaelson, J. Neurochem., vol. 7, No. 2, pp. 708-714, (1998)). Thus apolipoprotein E is considered to play a role essential for the maintenance of central nervous system.
It has been reported that an administration of apolipoprotein E to apolipoprotein E-deficient mice provides a remarkable improvement in the learning capacity and restoration of neuronal structure, which suggests that apolipoprotein E plays a neurotrophic effect to maintain and restore the nervous systems in vivo, and that it is useful in the treatment of human neurodegenerative diseases (see E. Masliah et al., Brain Res. 751, pp. 307-314, (1997)).
In view of the foregoing facts, it has been desired to elucidate drugs of increasing a plasma apolipoprotein E level for a method of treating hyperlipemia, especially familial hypercholesterolemia homozygote which has been considered to be difficult to treat with prior drugs.
Further, it has been desired to elucidate drugs which promote the repair and growth of the nervous system and inhibit the disintegration of the central nervous system, for an agent for the treatment of a new type of senile dementia. This may be accomplished by promoting the production of apolipoprotein E.
Under such circumstances, the present inventors have studied in an effort to provide the agents for promoting the production of apolipoprotein E, and found that depsipeptide derivatives having a specific structure possess the above function.